Twenty three Flashcards
Define pain, both nociceptive and neurpathic. Define nociception, analgesia, hyperalgesia, and allodynia.
— Pain = sensory experience that injures or threatens to destroy tissue
— Nociceptive (somatic or visceral) (actually destroys tissue)
— Neuropathic (pressure on nerves)
— Nociception = activation of afferent fibers that
transmit painful stimuli
— Analgesia = reduced sensitivity to pain
— Hyperalgesia = enhanced sensitivity to pain
— Allodynia = pain evoked by a normally non-noxious
stimulus
What are nociceptors like? What are their axons like? What is meant by the fact that they convey unimodal information? What kind of stimuli do they respond to?
All nociceptors observed thus far are free (“undifferentiated”) nerve endings. Nociceptive information is carried by unmyelinated C fibers and small myelinated (A-delta) fibers. In humans virtually 100% of all unmyelinated C fibers are nociceptive neurons.
- The majority of nociceptive afferent fibers convey unimodal information to the CNS. Most receptors are sensitive to only one form of a damaging physical stimulus. Thus, there are receptors that can be activated most readily by one of the following:
a) noxious mechanical stimuli
b) noxious chemical stimuli
c) noxious heat stimuli
d) noxious cold stimuli (possibly)
What causes depolarization of nociceptors? What are some examples? What do they do?
- The specificity of each type of nociceptor is mediated by unknown mechanisms. Although the cause of depolarization to specific nociceptive stimuli is not clear, it is likely to involve release of different chemical substances. For example, in the skin there are several chemical substances, which either depolarize or sensitize afferent fibers (Fig. 1A). These include K+other peptides, prostaglandins and leukotrienes. Some of these chemicals
rarely depolarize the primary afferent neuron but lower the membrane potential thereby increasing their excitability. Therefore, it is likely that different noxious stimuli cause release of different chemical mediators that depolarize or sensitize specific populations of primary afferents. The
neurotransmitters in primary afferents can be separated into those mediating fast responses including glutamate, and those mediating slow, sustained responses such as substance P, vasoactive intestinal polypeptide (VIP), somatostatin and other peptides. ions, histamine, bradykinin, serotonin, (substance P), P2X family of channels (ATP),TRP (transient receptor potential) channels (Temperature sensitive), ASIC (acid sensing ion channels) (Acidosis,Inflammation)
What happens in prolonged damage to peripheral nociceptors?
- Prolonged damage to peripheral nociceptors can produce sustained sensitization resulting in hyperalgesia. Hyperalgesia is either due to a lower threshold for activation or an increase in the response of the primary
afferent (manifest by more action potentials). Hyperalgesia at the site of the injury (primary hyperalgesia) and even, possibly, in the surrounding tissue (secondary hyperalgesia) is likely to be mediated by one or more of
the chemical mediators mentioned above. In some cases, alterations to primary nociceptive afferents may result in allodynia.
What is visceral pain usually like? What is referred pain and what causes it?
- Visceral pain is poorly understood. This type of pain is more commonly associated with sustained dull pain (paleospinothalamic tract) having a more pronounced affective component. In contrast, sharp pain arising
from visceral organs (e.g. cardiac angina, ureteral or biliary obstruction) is described as particularly excruciating in many cases. Visceral nociception is different from cutaneous nociception in that it is very difficult to localize the source of pain from internal organs. Instead, visceral pain is perceived as arising from a relatively large dermatome on the surface of the body. This is called “referred pain”. In 1955, Ruch proposed that referred pain was a result of convergence of nociceptive afferents from
internal organs onto the same dorsal horn neurons receiving cutaneous input rather than a result of neurons with axonal branches from visceral and cutaneous sites. In fact, both types of input have been verified recently but the vast majority of visceral afferents are not branched, i.e.
they simply project to dorsal horn neurons that receive cutaneous input from other afferents. Therefore, Ruch’s original hypothesis explains the convergence of input that result in referred pain for all practical purposes.
What is phantom limb pain and how does it happen? What is causalgia and how can it be prevented?
- Activation of nociceptive afferents can occur even after nerve damage or complete axonal transection. Phantom limb pain has been described in patients after amputation. In this case, either transected afferents or dorsal horn neurons are activated leading the patient to perceive pain in a missing limb. Injury to a nerve can also lead to inappropriate activation of dorsal horn neurons causing the perception of pain. In some cases, the pain arises from inadvertent activation of adjacent sympathetic nerves in the region of the injury. This pain, called causalgia can be prevented by blocking the sympathetic nervous system.
Explain the gate control theory.
Small primary afferents (A-delta and C fibers) pass through the tract of Lissauer, and terminate on large marginal cells (lamina I) or on lamina V neurons (usually C fiber input). Larger primary afferents (A-beta) send collaterals to synapse diffusely onto cells in the substantia
gelatinosa (lamina II). This differential distribution of primary afferent terminals formed the basis of the “Inhibitory Balance Theory of Pain” proposed by Kerr. A more recent modification of this theory, proposed by Melzack and Wall, is called the gate control theory (fig. 1B). Neurophysiological experiments have demonstrated that substantia gelatinosa cells are often inhibitory to spinothalamic projection neurons. Consequently when lamina V cells are activated by nociceptive stimuli
through small fibers, simultaneous stimulation of large primary afferents (A-beta) inhibits these neurons. Therefore, the nociceptive input is reduced. Large afferents have a low threshold but are fast adapting
whereas small nociceptive afferents have a high threshold but are slow-adapting so complete, long-lasting analgesia does not occur. Therefore, larger primary afferents inhibit input from the smaller afferents thereby reducing the intensity of nociceptive stimulus perceived.
What are low threshold nociceptors? High threshold? Wide dynamic range?
Neurons receiving nociceptive input are classified as low threshold (activated by relatively innocuous stimuli), high threshold (activated only by stimuli considered quite painful) and wide dynamic range or multimodal. The latter neurons are found in deeper laminae (IV and V) and respond to all forms of mechanical stimulation from innocuous touch (low firing rate) all the way to damaging mechanical stimuli (fastest frequency). They receive input from both unmyelinated and myelinated nociceptive afferents. In humans when specifically stimulated, they are
fully capable of providing a painful sensation, but the sensation is complex and may integrate more than one modality. Some wide dynamic range neurons also receive convergent input from visceral organs. These are likely to be responsible for referred pain (see above).
Describe the spinothalamic tract, spinoreticular tract, spinomesencephalic tract, spinocervical tract, and spinobulbar tract. and the trigeminal system.
a) Spinothalamic tract: The largest tract arising from lamina I and V-VII, it carries nociceptive and wide dynamic range input and ascends in the contralateral anterolateral white matter to the central lateral nucleus and ventral posterior lateral nucleus of the thalamus.
b) Spinoreticular tract: This tract begins in deeper lamina (VII-VIII) and ascends in the contralateral anterolateral spinal cord to the reticular formation of the brain stem. While most fibers ascend contralaterally, some fibers ascend ipsilaterally and some project both to the reticular formation and to the thalamus (branching fibers).
c) Spinomesencephalic tract: Neurons from lamina I and V
project to the mesencephalic reticular formation, the periaqueductal gray and other mesencephalic sites.
d) Spinocervical tract: Some small neurons in lamina III and IV send nociceptive input to neurons in the lateral cervical nucleus in the cervical spinal cord. These neurons, in turn, cross the midline and project to the thalamus.
e) Spinobulbar tract: A small number of neurons in lamina III and IV project through the dorsal columns to the cuneate and gracile nuclei in the brain stem.
- The trigeminothalamic system is both homologous and analogous to the lateral spinothalamic tract. Neurophysiological studies have revealed that neurons
arising from the rostral parts of the trigeminal nuclear complex convey light tactile information to the VPM nucleus of the thalamus. The pars caudalis carries nociceptive information from the face to the brainstem reticular formation and to the intralaminar and ventral posterior nuclei.
What is SPA? How does it work? What are some sites of it? What are some NTs involved in pain transmission and modulation?
It has been shown in humans and animals that stimulation of discrete sites in the CNS (e.g., periaqueductal gray, mesencephalic dorsal raphe or raphe magnus, locus coreoleus, lateral hypothalamus) reduces the responses of dorsal horn neurons to nociceptive afferent stimuli. This has been named stimulation-produced analgesia (SPA). In fact, Reynolds demonstrated that stimulation of the PAG in rats results in sufficient analgesia to perform a laparotomy. In humans with intractable pain syndromes, stimulation of the periventricular gray region, the ventrobasal thalamus or the internal capsule has been found to be effective in controlling the pain. Proprioception is not altered significantly in these patients. The descending projections mediating SPA contain serotonin, norepinephrine and GABA. Several sites in the CNS can modulate nociceptive input due to projections to lamina I and V.
— Norepinephrine (excitatory)
— Serotonin (inhibitory)
— GABA
— Glycine
— Cholecystokinin (CCK)
— Somatostatin (SST)
— Neurotensin (Nt)
— Endogenous opiates
What are 3 types of opiod receptors? What are 3 types of endogenous opiates? How do they work?
Several peptides have been identified that act on opiate receptors to suppress nociceptive input at both spinal and supraspinal levels. Some of these are called endogenous opiates since they act on the same receptors as opiate analgesics. Furthermore, at least three receptors for endogenous opiates have been characterized and recently cloned; delta, mu and kappa receptors. Hughes and Kosterlitz first identified enkephalins as endogenous opioids in 1975. These compounds are pentapeptides that preferentially bind to both mu and delta opioid receptors. Subsequently, the endorphins were identified that acted somewhat selectively on the mu receptors. These are the receptors most sensitive to morphine. Finally, by 1979 a third class of endogenous opiates was identified and named dynorphins. Dynorphins preferentially act on kappa receptors.
The endogenous opioids reduce pain sensitivity typically by pre- or postsynaptic inhibition of critical relay sites for nociceptive input. Therefore, in addition to the neurotransmitters described earlier (serotonin, norepinephrine, GABA), these neurotransmitters modulate nociceptive input selectively.
What are some examples of how to control pain?
— Drug therapy — Opiate analgesics — Non-opiate analgesics — Anesthetics — Toxins
— Surgery
— Cordotomy
— Rhizotomy,
— Thalatomy
— Stimulation (e.g. SPA) CNS stimulation (PAG, NRM, PRF) Spinal cord stimulation (SCS) – back & limbs Peripheral nerve stimulation (TENS) Acupuncture
